A seeming paradox exists during the maintenance phase of acute renal failure (ARF). On the one hand, diverse forms of acute tubular injury evoke adaptive responses that protect the kidney from further damage (so called acquired cytoresistance). Presumably, this protection confers a survival advantage, both at the whole organ, and whole animal, level. On the other hand, a potentially countervailing consequence of ARF is that the kidney hyper-responds to diverse Toll like receptor (TLR) ligands, most notably lipopolysaccharide (LPS). This causes exaggerated LPS- driven cytokine and chemokine (e.g., TNF-a / MCP- 1) production. As a result, profound increases in intra-renal levels of these pro-inflammatory mediators develop, potentially slowing ARF recovery. Furthermore, with cytokine efflux into renal venous blood, striking increases in circulating cytokine / chemokine levels develop. This can contribute to extra-renal tissue damage (e.g., in lung, liver, heart, and brain; i.e., organ cross-talk), and thus, predispose to multi-organ failure (MOF). The clinical relevance of these events is underscored by the fact that Gram negative sepsis and MOF are leading causes of death in patients with ARF. This application hypothesizes that these two ARF maintenance phase phenomena (cytoresistance; TLR hyper-responsiveness) are examples of biologic memory: i.e., whereby one episode of renal injury 're-programs' the kidney to 'remember' the initial insult, and thus, produce altered tissue responses upon re-challenge. Over the past 3 years, the PI has tested the hypothesis that this biologic memory is expressed at the genomic level, and that these genomic changes help determine how the ARF kidney responds to subsequent insults. To support this concept, we have identified activating histone changes at specific genes that participate in both acquired cytoresistance (heme oxygenase 1, HMG CoA reductase), and the hyper-inflammatory state (TNF-a; MCP-1). During the resolution phase of ARF, the histone changes at these pro-inflammatory genes and their cognate mRNAs progressively increase. Conversely, cytoresistant gene expression progressively abates. These reciprocal shifting patterns, i.e., increasing inflammatory gene expression / decreasing cytoresistance gene expression, can delay ARF recovery. Hence, the overall aims of the proposed investigation are as follows: 1. Delineate which specific cell injury pathways (e.g., ATP depletion, oxidant stress, phospholipid hydrolysis) are the initial stimuli that trigger downstream histone alterations; 2. Determine whether histone changes occur at test gene promoter regions, and whether hyper-recruitment of relevant transcription factors and of RNA polymerase II (Pol II) to them result; 3. Ascertain the histone-modifying machineries that induce these histone alterations; and 4. Using the information gleaned from the above, test the mechanistic relevance of these pathways to the cytoresistance and the hyper-inflammatory states. By so doing, new insights into ischemia- induced tissue modifications, with implications for subsequent tissue injury, will result.